Insecticidal N-substituted (heteroaryl)alkyl sulfilimines

ABSTRACT

N-Substituted (heteroaryl)alkyl sulfilimines are effective at controlling insects.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/841,934 filed on Sep. 1, 2006.

BACKGROUND OF THE INVENTION

The present invention concerns novel N-substituted (heteroaryl)alkylsulfilimines and their use in controlling insects, particularly aphidsand other sucking insects, as well as certain other invertebrates. Thisinvention also includes new synthetic procedures for preparing thecompounds, pesticide compositions containing the compounds, and methodsof controlling insects using the compounds.

There is an acute need for new insecticides. Insects are developingresistance to the insecticides in current use. At least 400 species ofarthropods are resistant to one or more insecticides. The development ofresistance to some of the older insecticides, such as DDT, thecarbamates, and the organophosphates, is well known. But resistance haseven developed to some of the newer pyrethroid insecticides. Therefore aneed exists for new insecticides, and particularly for compounds thathave new or atypical modes of action.

SUMMARY OF THE INVENTION

This invention concerns compounds useful for the control of insects,especially useful for the control of aphids and other sucking insects.More specifically, the invention concerns compounds of the formula (I)

wherein

Het represents:

X represents halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₂-C₄ haloalkenyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, CN, NO₂,SO_(m)R⁶ where m is an integer from 0-2, COOR⁴ or CONR⁴R⁵;

Y represents hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkenyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, CN, NO₂, SO_(m)R¹ where m is an integer from 0-2, COOR⁴,CONR⁴R⁵, aryl or heteroaryl;

Z represents C₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄haloalkenyl, C₁-C₄ haloalkoxy, CN, NO₂, SO_(m)R¹ where m is an integerfrom 0-2, COOR⁴ or CONR⁴R⁵;

n is an integer from 0-3;

L represents either a single bond, —CH₂—, or —CH(CH₂)_(p)— where p is aninteger from 1-3 and either R¹, S and L or R², L and the common carbonto which they attach are taken together to represent a 4-, 5-, or6-membered ring with up to, but no more than, 1 heteratom;

R¹ represents C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, C₃-C₆ haloalkenyl, arylalkyl, heteroarylalkyl, or,alternatively, is taken together with either L or R² to form a saturated4-, 5-, or 6-membered ring;

R² and R³ independently represent hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkenyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, CN, SO_(m)R⁶ where m is an integer from 0-2,COOR⁴, CONR⁴R⁵, arylalkyl, heteroarylalkyl, or, alternatively, R² and R³and the common carbon to which they attach form a 3-6 membered ring, orR² and R¹ taken together form a saturated 4-, 5-, or 6-membered ring;

R⁴ and R⁵ independently represent hydrogen, C₁-C₄ alkyl, C₁-C₄haloalkyl; C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ haloakenyl, aryl,heteroaryl, arylalkyl or heteroarylalkyl;

R⁶ represents C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, C₃-C₆ haloalkenyl, arylalkyl, heteroarylalkyl; and

Q represents NO₂ or CN.

Preferred compounds of formula (I) include the following classes:

(1) Compounds of formula (I) wherein Het is (6-substituted)pyridine-3-ylor (2-substituted)thiazol-5-yl and where Z is C₁-C₂ haloalkyl and Y ishydrogen;

(2) Compounds of formula (I) wherein R² and R³ are as previouslydefined, R¹ is methyl, n is 1, and L is a single bond, having thestructure:

(3) Compounds of formula (I) wherein n is 1, R¹, S and L taken togetherform a standard 4-, 5-, or 6-membered ring such that L is —CH(CH₂)_(p)—,and R¹ is —CH₂— having the structure:

(4) Compounds of formula (I) wherein n is 0, R¹, S and L taken togetherform a standard 4-, 5-, or 6-membered ring such that L is —CH(CH₂)_(p)—,and R¹ is —CH₂— having the structure:

(5) Compounds of formula (I) where Q is CN;

It will be appreciated by those skilled in the art that the mostpreferred compounds are generally those which are comprised ofcombinations of the above preferred classes.

The invention also provides new processes for preparing compounds offormula (I) as well as new compositions and methods of use, which willbe described in detail hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this document, all temperatures are given in degrees Celsius,and all percentages are weight percentages unless otherwise stated.

The terms “alkyl”, “alkenyl” and “alkynyl”, as well as derivative termssuch as “alkoxy”, “acyl”, “alkylthio”, “arylalkyl”, “heteroarylalkyl”and “alkylsulfonyl”, as used herein, include within their scope straightchain, branched chain and cyclic moieties. Thus, typical alkyl groupsare methyl, ethyl, 1-methyl-ethyl, propyl, 1,1-dimethylethyl, andcyclopropyl. Unless specifically stated otherwise, each may beunsubstituted or substituted with one or more substituents selected frombut not limited to halogen, hydroxy, alkoxy, alkylthio, C₁-C₆ acyl,formyl, cyano, aryloxy or aryl, provided that the substituents aresterically compatible and the rules of chemical bonding and strainenergy are satisfied. The term “haloalkyl” and “haloalkenyl” includesalkyl and alkenyl groups substituted with from one to the maximumpossible number of halogen atoms, all combinations of halogens included.The term “halogen” or “halo” includes fluorine, chlorine, bromine andiodine, with fluorine being preferred. The terms “alkenyl” and “alkynyl”are intended to include one or more unsaturated bonds.

The term “aryl” refers to a phenyl, indanyl or naphthyl group. The term“heteroaryl” refers to a 5- or 6-membered aromatic ring containing oneor more heteroatoms, viz., N, O or S; these heteroaromatic rings may befused to other aromatic systems. The aryl or heteroaryl substituents maybe unsubstituted or substituted with one or more substituents selectedfrom halogen, hydroxy, nitro, cyano, aryloxy, formyl, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, halogenated C₁-C₆ alkyl,halogenated C₁-C₆ alkoxy, C₁-C₆ acyl, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, aryl, C₁-C₆OC(O)alkyl, C₁-C₆NHC(O)alkyl, C(O)OH, C₁-C₆ C(O)Oalkyl, C(O)NH₂, C₁-C₆ C(O)NHalkyl, orC₁-C₆ C(O)N(alkyl)₂, provided that the substituents are stericallycompatible and the rules of chemical bonding and strain energy aresatisfied.

The compounds of this invention can exist as one or more stereoisomers.The various stereoisomers include geometric isomers, diastereomers andenantiomers. Thus the compounds of the present invention include racemicmixtures, individual stereoisomers and optically active mixtures. Itwill be appreciated by those skilled in the art that one stereoisomermay be more active than the others. Individual stereoisomers andoptically active mixtures may be obtained by selective syntheticprocedures, by conventional synthetic procedures using resolved startingmaterials or by conventional resolution procedures.

The compounds of formula (I), wherein Q is NO₂ and R¹, R², R³, n, and Lare as previously defined can be prepared by the method illustrated inScheme A.

In step a of Scheme A, sulfide of formula (A) is reacted with nitramidein the presence of acetic anhydride to provide the sulfilimine (I).(Shitov, O. P.; Seleznev, A. P; Tartakovski, V. A. Inst. Org. Kim. im.Zelinskogo, Moscow, USSR. Izvestiya Akademii Nauk SSSR, SeriyaKhimicheskaya (1991), (5), 1237-8.)

The compounds of formula (Ia), wherein Q is CN and Het, R¹, R², R³, n,and L are as previously defined can be prepared by the methodillustrated in Scheme B. Accordingly, the precursor sulfide is oxidizedwith iodobenzene diacetate in the presence of cyanamide at 0° C. to givesulfilimine (Ia). The reaction can be carried out in a polar aproticsolvent like CH₂Cl₂.

The precursor sulfides (A) can, in turn, be prepared in different waysas illustrated in Schemes C, D, E, F and G.

In Scheme C, the sulfide of formula (A₁), wherein L is a single bond, nis 1, R³=H, and R¹, R² and Het are as previously defined can be preparedfrom halides of formula (D) by nucleophilic substitution with the sodiumsalt of an alkyl thiol.

In Scheme D, the sulfide of formula (A₂), wherein L is a single bond, nis 3, R³=H, and R¹, R² and Het are as previously defined, can beprepared from the chloride of formula (E) by reacting with a 2-monosubstituted methyl malonate in the presence of base such as potassiumtert-butoxide to provide 2,2-disubstituted malonate, hydrolysis underbasic conditions to form a diacid, decarboxylation of the diacid byheating to give a monoacid, reduction of the monoacid withborane-tetrahyrofuran complex to provide an alcohol, tosylation of thealcohol with toluenesulfonyl chloride (tosyl chloride) in the presenceof a base like pyridine to give a tosylate and replacement of thetosylate with the sodium salt of the desired thiol.

In Scheme E, the sulfide of formula (A₃), wherein L is a single bond, nis 2, R³=H, and R¹, R² and Het are as previously defined, can beprepared from the nitrile of formula (F) by deprotonation with a strongbase and alkylation with an alkyl iodide to give α-alkylated nitrile,hydrolysis of the α-alkylated nitrile in the presence of a strong acidlike HCl to give an acid, reduction of the acid withborane-tetrahyrofuran complex to provide an alcohol, tosylation of thealcohol with tosyl chloride in the presence of a base like pyridine togive a tosylate and replacement of the tosylate with the sodium salt ofthe desired thiol.

In Scheme F, the sulfide of formula (A₄), wherein n is 0, R¹ is —CH₂—, Lis —CH(CH₂)_(p)— where p is either 2 or 3 and, taken together with R¹, Sand L form a 5- or 6-membered ring, and Het is as previously describedcan be prepared from tetrahydrothiophene (p=2) or pentamethylene sulfide(p=3) (G). Chlorination of the cyclic sulfide starting material withN-chlorosuccinimide in benzene followed by alkylation with certainlithiated heterocycles or Grignard reagents can lead to the desiredsulfides (A₄) in satisfactory yield.

A more efficient protocol to access cyclic sulfides of formula (A₄) isillustrated in Scheme G where Het is a 6-substituted pyridin-3-yl and Zis previously defined. Accordingly, thiourea is added to a substitutedchloromethyl pyridine, which, after hydrolysis, and alkylation with theappropriate bromo chloroalkane (p=1, 2, or 3) under aqueous baseconditions, yields sulfide (H). Subsequent cyclization of (H) in thepresence of a base like potassium-t-butoxide in a polar aprotic solventsuch as THF provides cyclic sulfide (A₄).

Certain sulfides of formula (A₁) wherein Het is a substitutedpyridin-3-yl, Z is as previously defined, and R¹, R²=CH₃ can be preparedalternatively via methods illustrated in Scheme H. Accordingly, theappropriate enone is coupled with dimethylaminoacrylonitrile andcyclized with ammonium acetate in DMF to yield the corresponding6-substituted nicotinonitrile. Treatment with methyl-magnesium bromide,reduction with sodium borohydride, chlorination with thionyl chloride,and nucleophilic substitution with the sodium salt of an alkyl thiolprovides desired sulfides (A₁).

A variation of Scheme H is illustrated in Scheme I, wherein enamines,formed from the addition of an amine, e.g., pyrrolidine, with theMichael adduct of certain sulfides with appropriately substitutedα,β-unsaturated aldehydes, are coupled with substituted enones andcyclized with ammonium acetate in CH₃CN to yield the desired sulfides(A₁) wherein R¹, R², R³, and Z are previously defined.

A variation of this method, illustrated in Scheme J, can be used toprepare cyclic pyridyl sulfides A₅ wherein n=1, L=—(CH₂)—, and R¹, R²connect to form a 5-membered ring. Accordingly, reaction oftetrahydrothiophen-3-one with triphenylphosphine and dimethyl-carbonateprovides the corresponding olefin, which is then hydroformylated withhydrogen and carbon monoxide in the presence of a rhodium catalyst atelevated pressure to afford aldehyde (N). Remaining steps to convert thealdehyde to sulfide (A₅) follows the same protocol as previouslydescribed in Scheme I.

In Scheme K sulfides of formula (A₆) wherein R¹ and Z are as previouslydefined, n=1 and L, R², and the common carbon they connect to are takentogether to form a 4-, 5-, or 6-membered ring (x=0-2) can be preparedfrom 2-substituted 5-bromo-pyridines via a halogen metal exchange witheither isopropyl Grignard or n-butyl lithium followed by addition tocyclic ketone such as cyclopentanone (x=1), dehydration to the olefinunder acidic conditions, hydroboration (borane in tetrahydrofuran),oxidative cleavage (sodium hydroxide and hydrogen peroxide), conversionof the resulting alcohol to a easily displaceable moiety such as amethanesulfonyl group (by treatment with methanesulfonyl chloride andtriethyl amine), and finally nucleophilic substitution with the sodiumsalt of an alkyl thiol.

EXAMPLES Example I Preparation of{1-[6-(trifluoromethyl)pyridin-3-yl]methyl}(methyl)-λ⁴-sulfanylidenecyanamide(1)

To a solution of 3-chloromethyl-6-(trifluoromethyl)pyridine (5.1 g, 26mmol) in dimethyl sulfoxide (DMSO; 20 mL) was added sodium thiomethoxidein one portion (1.8 g, 26 mmol). A violent exothermic reaction wasobserved which resulted in the reaction turning dark. The reaction wasstirred for 1 hr, then additional sodium thiomethoxide (0.91 g, 13 mmol)was added slowly. The reaction was stirred overnight, after which it waspoured into H₂O and several drops of conc. HCl were added. The mixturewas extracted with Et₂O (3×50 mL) and the organic layers combined,washed with brine, dried over MgSO₄, filtered, and concentrated. Thecrude product was purified by chromatography (Prep 500, 10%acetone/hexanes, v/v) to furnish the sulfide (A) as a pale yellow oil(3.6 g, 67%). ¹H NMR (300 MHz, CDCl₃) δ 8.6 (s, 1H), 7.9 (d, 1H), 7.7(d, 1H), 3.7 (s, 2H), 2.0 (s, 3H); GC-MS: mass calcd for C₈H₈F₃NS [M]⁺207. Found 207.

To a solution of sulfide (A) (3.5 g, 17 mmol) and cyanamide (1.4 mg, 34mmol) in CH₂Cl₂ (30 mL) at 0° C. was added iodobenzenediacetate (11.0 g,34 mmol) all at once. The reaction was stirred for 30 min and thenallowed to warm to room temperature overnight. The mixture was dilutedwith CH₂Cl₂ (50 mL) and washed with H₂O. The aqueous layer was extractedwith ethyl acetate (4×50 mL), and the combined CH₂Cl₂ and ethyl acetatelayers dried over MgSO₄ and concentrated. The crude product wastriturated with hexanes and purified by chromatography (chromatotron,60% acetone/hexanes, v/v) to furnish the sulfilimine (1) as a yellow gum(0.60 g, 14%). IR (film) 3008, 2924, 2143, 1693 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) δ 8.8 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 4.5 (d, 1H), 4.3 (d,1H), 2.9 (s, 3H); LC-MS (ESI): mass calcd for C₉H₉F₃N₃S [M+H]⁺ 248.04.Found 248.

Example II Preparation of(1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethyl)(methyl)-λ⁴-sulfanylidenecyanamide(2)

(3E)-1-Chloro-4-ethoxy-1,1-difluorobut-3-en-2-one (7.36 g, 40 mmol) wasdissolved in dry toluene (40 mL) and treated with3-dimethylaminoacrylonitrile (4.61 g, 48 mmol) at room temperature. Thesolution was heated at about 100° C. for 3.5 hr. The solvent was thenremoved under reduced pressure and the remaining mixture wasre-dissolved in dimethyl formamide (DMF; 20 mL), treated with ammoniumacetate (4.62 g, 60 mmol) and stirred at room temperature overnight.Water was added to the reaction mixture and the resulting mixture wasextracted with ether-CH₂CH₂ (1:2, v/v) twice. The combined organic layerwas washed with brine, dried, filtered and concentrated. The residue waspurified on silica gel to give 3.1 g of6-[chloro(difluoro)methyl]nicotinonitrile (A) as light colored oil in41% yield. GC-MS: mass calcd for C₇H₃ClF₂N₂ [M]⁺ 188. Found 188.

6-[Chloro(difluoro)methyl]nicotinonitrile (A) (3.0 g, 15.8 mmol) wasdissolved in anhydrous ether (25 mL) and cooled in an ice-water bath. Asolution of 3 M of methylmagnesium bromide in hexane (6.4 mL, 19 mmol)was added through a syringe. After the addition was over, the mixturewas stirred at 0° C. for 5 hr and then at room temperature for 10 hr.The reaction was quenched slowly with 1 N citric acid aqueous solutionat 0° C. and the resulting mixture was stirred at room temperature for 1hr. The pH was adjusted back to pH 7 with saturated aqueous NaHCO₃solution. The two phases were separated and the aqueous phase wasextracted with ethyl acetate twice. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The remaining mixture was purified on silica gel elutedwith 15% acetone in hexane (v/v) to give 0.88 g of the desired product1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethanone (B) as brownish oilin 30% yield. GC-MS: mass calcd for C₈H₆ClF₂NO [M]⁺ 205. Found 205.

To a solution of 1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethanone (B)(0.85 g, 4.14 mmol) in MeOH (10 mL) at 0° C. was added NaBH₄ (0.16 g,4.14 mmol). The mixture was stirred for 30 min and 2 M HCl aqueoussolution was added until pH reached 7. Solvent was removed under reducedpressure and the remaining mixture was extracted with CH₂Cl₂ (2×50 mL).The combined organic layer was dried over anhydrous Na₂SO₄, filtered,concentrated, and dried in vacuo to give 0.798 g of analytically pure1-{6-[chloro(difluoro)methyl]-pyridin-3-yl}ethanol (C) on GC-MS as alight yellow oil in 93% yield. GC-MS: mass calcd for C₈H₆ClF₂NO [M]⁺207. Found 207.

To a solution of 1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethanol (0.78g, 3.77 mmol) in CH₂Cl₂ (40 mL) was added thionyl chloride (0.54 mL,7.54 mmol) dropwise at room temperature. After 1 hr, the reaction wasquenched slowly with saturated NaHCO₃ aqueous solution and the twophases were separated. The organic layer was dried over Na₂SO₄,filtered, concentrated, and dried in vacuum to give 0.83 g of the crude2-[chloro(difluoro)methyl]-5-(1-chloroethyl)pyridine (D) as brown oil in98% yield, which was directly used for the next step reaction. GC-MS:mass calcd for C₈H₇Cl₂F₂N [M]⁺ 225. Found 225.

To a solution of 2-[chloro(difluoro)methyl]-5-(1-chloroethyl)pyridine(D) (0.81 g, 3.6 mmol) in ethanol (10 mL) was added sodium thiomethoxide(0.52 g, 7.4 mmol) under stirring in one portion at 0° C. After 10 min,the mixture was allowed to warm to room temperature and stirredovernight. The solvent ethanol was then removed under reduced pressureand the residue was re-taken into ether/CH₂Cl₂ and brine. The two phaseswere separated and the aqueous layer was extracted with CH₂Cl₂ one moretime. The combined organic layer was dried over anhydrous Na₂SO₄,filtered, concentrated, and purified on silica gel using 5% ethylacetate in hexane (v/v) to give 0.348 g of the2-[chloro(difluoro)methyl]-5-[1-(methylthio)ethyl]pyridine (E) in 40%yield GC-MS: mass calcd for C₉H₁₀ClF₂NS [M]⁺ 237. Found 237.

To a stirred solution of2-[chloro(difluoro)methyl]-5-[1-(methylthio)-ethyl]pyridine (E) (0.32 g,1.35 mmol) and cyanamide (0.058 g, 1.35 mmol) in tetrahydrofuran (THF; 7mL) was added iodobenzene diacetate (0.44 g, 1.35 mmol) in one portionat 0° C. and the resulting mixture was stirred at this temperature for 1hr and then at room temperature for 2 hr. The solvent was removed underreduced pressure and the resulting mixture was dissolved in CH₂Cl₂,washed with half-saturated brine, dried over anhydrous Na₂SO₄, filtered,concentrated, and purified on silica gel using 50% acetone in hexane(v/v) to give 0.175 g of(1-{6-[chloro-(difluoro)methyl]pyridin-3-yl}ethyl)(methyl)-λ⁴-sulfanylidenecyanamide(2) as a light-yellow oil in 48% yield. ¹H NMR (300 MHz, CDCl₃) δ 8.71(d, J=1.8 Hz, 1H), 7.91 (dd, J=8.4, 1.8 Hz, 1H) 7.78 (d, J=8.4 Hz, 1H),4.42 (q, J=6.9 Hz, 1H), 2.64 (s, 3H), 1.92 (d, J=6.9 Hz, 3H); LC-MS:mass calcd for C₁₀H₁₀ClF₂N₃S [M+1]⁺ 278. Found 278.

Example III Preparation of{1-[6-(trichloromethyl)pyridin-3-yl]ethyl}(methyl)-λ⁴-sulfanylidenecyanamide(3)

A mixture of 5-ethylpyridine-2-carboxylic acid (1.98 g, 13 mmol),phenyl-phosphonic dichloride (2.8 g, 14.3 mmol), phosphoruspentachloride (7.7 g, 32 mmol) was stirred and slowly heated. Once aclear yellow liquid was formed, the mixture was heated to refluxovernight. After cooling, the volatiles were removed under reducedpressure. The residue was carefully poured into saturated sodiumcarbonate aqueous solution cooled in an ice-water bath. The aqueousphase was then extracted with CH₂Cl₂ twice. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄, filtered,concentrated, and partially purified on silica gel eluted with 10% EtOAcin hexane (v/v) to give 2.7 g of crude product containing both5-ethyl-2-(trichloromethyl)pyridine and5-(1-chloroethyl)-2-(trichloromethyl)pyridine in an approximate 3:1ratio (GC data, masses calcd for C₈H₈Cl₃N and C₈H₇Cl₄N [M]⁺ 223 and 257respectively. Found 223 and 257 respectively).

A mixture of the above-mentioned crude product (2.6 g) in carbontetrachloride (100 mL) was treated with ca 80% of N-bromosuccinimide(1.9 g, 11 mmol) and benzoylperoxide (0.66 g, 0.275 mmol) and refluxedovernight. The solid was filtered off, the filtrate concentrated and theresulting residue purified on silica gel using 4% EtOAc in hexane (v/v)to give 1.0 g of the desired product5-(1-bromoethyl)-2-(trichloromethyl)pyridine (A) as a yellow solid. Thecombined yield for the two steps was 25%. GC-MS: mass calcd forC₈H₇BrCl₃N [M−1−Cl]⁺ 266. Found 266.

A solution of 5-(1-bromoethyl)-2-(trichloromethyl)pyridine (A) (0.95 g,3.14 mmol) in ethanol (15 mL) was treated with sodium thiomethoxide(0.44 g, 6.29 mmol) portionwise at 0° C. The mixture was stirred at roomtemperature overnight. The solvent ethanol was then removed under areduced pressure and the residue was re-taken into CH₂Cl₂ and brine. Thetwo phases were separated and the organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified on silicagel using 5% EtOAc in hexane v/v to give 0.57 g of the partially pure5-[1-(methylthio)ethyl]-2-(trichloromethyl)pyridine (B) in 67% crudeyield. GC-MS: mass calcd for C₉H₁₀Cl₃NS [M]⁺ 269. Found 269.

To a stirred solution of5-[1-(methylthio)ethyl]-2-(trichloromethyl)-pyridine (B) (0.55 g, 2.3mmol) and cyanamide (0.097 g, 2.3 mmol) in THF (7 mL) cooled to 0° C.was added iodobenzene diacetate (0.75 g, 2.3 mmol) in one portion. Theresulting mixture was stirred at 0° C. for 1 hr and then at roomtemperature for 2 hr. The solvent was removed in vacuo and the resultingmixture was purified on silica gel using 50% acetone in hexane (v/v) togive 0.254 g of{1-[6-(trichloromethyl)pyridin-3-yl]ethyl}(methyl)-λ⁴-sulfanylidenecyanamide(3) as an off-white solid in 40% yield. ¹H NMR for the diastereomericmixture (300 MHz, d₆-acetone) δ 8.87 (s, 1H), 8.21-8.25 (m, 2H),4.65-4.76 (m, 1H), 2.86-2.66 (m, 3H), 1.88-1.92 (m, 3H).

Example IV Preparation of(1E)-[1-(2-chloropyrimidin-5-yl)ethyl](methyl)-λ⁴-sulfanylidenecyanamide(4)

A solution of 2-chloro-5-ethylpyrimidine (1.15 g, 8.1 mmol) in 20 mL ofcarbon tetrachloride was treated with N-bromosuccinimide (1.50 g, 8.4mmol) and a catalytic amount of benzoyl peroxide and the mixture heatedto 75° C. After several hours and additional catalyst, the startingmaterial was completely consumed. The solid was removed and the filtrateconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel using a mixture of ethylacetate and petroleum ether as the eluting solvent. The solvents wereremoved under reduced pressure to yield 0.64 g (36%) of5-(1-bromoethyl)-2-chloropyrimidine (A) as a clear liquid: ¹H NMR(CDCl₃) δ 8.70 (s, 2H), 5.15 (q, J=8.0 Hz, 1H), 2.10 (d, J=8.0 Hz, 3H);GCMS (FID) m/z 222 (M+). Some of the corresponding dibromo compound 0.44g (18%) was also isolated, as a white solid: mp 84-85° C.; ¹H NMR(CDCl₃) d 9.00 (s, 2H), 3.00 (s, 3H); LCMS (ESI) m/z 298 (M+H).

2-Chloro-5-[1-(methylthio)ethyl]pyrimidine (B) was obtained as a paleyellow syrup from bromide (A) using the same procedure described inExample III (B) above. ¹H NMR (CDCl₃) δ 8.60 (s, 2H), 3.85 (q, J=8.0 Hz,1H), 1.98 (s, 3H), 1.65 (d, J=8.0 Hz, 3H); GCMS (FID) m/z 188 (M+).

Title compound(1E)-[1-(2-chloropyrimidin-5-yl)ethyl](methyl)-λ⁴-sulfanylidenecyanamide(4) was obtained as a pale orange syrup and a 2:1 mixture ofdiastereomers from sulfide (B) using the same procedure described inExample III (C) above. Major diastereomer: ¹H NMR (CDCl₃) δ 8.68 (s,2H), 4.38 q, J=8.3 Hz, 1H), 2.68 (s, 3H), 1.92 (d, J=8.3 Hz, 3H); LC-MS(ESI) m/z 229 (M+H).

Example V Preparation of(1E)-methyl{[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}-λ⁴-sulfanylidenecyanamide(5)

5-[(methylthio)methyl]-2-(trifluoromethyl)-1,3-thiazole (B) was obtainedas a pale orange liquid from5-(bromomethyl)-2-(trifluoromethyl)-1,3-thiazole (A) [U.S. Pat. No.5,338,856] using the same procedure described in Example III (B). ¹H NMR(CDCl₃) δ 7.75 (s, 1H), 3.90 (s, 2H), 2.10 (s, 3H); GC-MS (FID) m/z 213(M+).

(1E)-methyl{[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}-λ⁴-sulfanyl-idenecyanamidewas obtained as a pale yellow syrup from sulfide (B) using the sameprocedure described in Example III (C) above.: ¹H NMR (CDCl₃) δ 8.00 (s,1H), 4.60 (s, 2H), 2.85 (s, 3H); LCMS (ESI) m/z 254 (M+H).

Example VI Preparation of3-[6-(trifluoromethyl)pyridin-3-yl]tetrahydro-1H-1λ⁴-thien-1-ylidenecyanamide(6)

Tetrahydrothien-3-one (9.947 g, 97.37 mmol) was placed in a 250 mL Parrbomb. Triphenylphosphine (28.09 g, 108.0 mmol) was added followed byCH₃I (0.30 mL, 4.8 mmol) and dimethyl carbonate (10.0 mL, 119 mmol). Thereactor was purged with nitrogen and then heated for 3 hr at 175° C. Thereaction mixture was cooled to room temperature and purified byKugelrohr distillation to give 3-methylene-tetrahydrothiophene as acolorless liquid (7.65 g) which contained the desired olefin along withmethanol and benzene. The desired olefin was used without furtherpurification. ¹H NMR (CDCl₃) δ 4.77 (m, 1H, olefinic H), 4.72 (m, 1H,olefinic H), 2.63 (t, J=7 Hz, 2H, H5), 2.55 (s, 2H, H2), 2.41 (br t, J=7Hz, 2H, H4). ¹³C{¹H} NMR (CDCl₃) δ 107.3 (olefinic CH₂), 36.7, 35.2,30.4. GC-MS (EI): 100 [m]⁺.

3-Methylene-tetrahydrothiophene (5.88 g, as mixture with benzene andmethanol) was placed in a 25 mL Parr bomb which contained a magneticstir bar. Rh(CO)₂(acac) (149 mg, 0.58 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (355 mg, 0.61mmol) were added as solids. The reactor was sealed and purged with CObefore pressurizing to 350 psi. Hydrogen was then added to bring thetotal pressure to 700 psi. The reactor was heated to 80° C. withmagnetic stirring for 14 h. The reaction mixture was cooled to roomtemperature. GC-MS indicated the presence of a single aldehyderegioisomer along with benzene and methanol. No starting olefin wasevident. Solvent was removed under vacuum and the product(tetrahydrothien-3-yl acetaldehyde) was isolated by Kugelrohrdistillation (50° C./0.01 mm) as a colorless liquid (1.1 g). ¹H NMR(acetone-d₆) δ 9.76 (t, J=1.4 Hz, 1H, CH₂CHO), 2.97 (m, 1H), 2.83 (d,J=5.7 Hz, 1H), 2.80 (d, J=5.4 Hz, 1H), 2.62 (br s, 3H), 2.46 (m, 1H),2.17 (m, 1H), 1.61 (m, 1H). GC-MS (EI): 130 [m]⁺.

Neat tetrahydrothien-3-yl acetaldehyde (1.10 g, 8.45 mmol) was placed ina vial which was purged with nitrogen. The vial was cooled in an icebath, and solid K₂CO₃ (0.584 g, 4.23 mmol) was added. Neat pyrrolidine(1.70 mL) was added dropwise over 5 min. The ice bath was removed, andthe reaction mixture was stirred under N₂ for 20 h. GC-MS showed cleanformation of the desired enamine. The solid was washed with four 10 mLportions of ether. The combined ether extracts were evaporated undervacuum to give the intermediate enamine as a light yellow oil (1.617 g).3-Ethoxy-1-trifluoromethylpropenal (1.634 g, 9.72 mmol) was dissolved inanhydrous CH₃CN (5 mL) under nitrogen. The solution was cooled in an icebath. A solution of enamine (1.617 g) in 2 mL CH₃CN was added dropwiseover 10 min. The ice bath was removed and solution allowed to warm toroom temperature and continue to stir over 2 h. Ammonium acetate (1.407g, 18.25 mmol) was added and the reaction mixture was refluxed undernitrogen for 1 h. The solution was cooled to room temperature and CH₃CNwas evaporated under vacuum. The resulting red oil was purified bycolumn chromatography on silica with hexane-ethyl acetate to yield5-tetrahydrothien-3-yl-2-(trifluoromethyl)pyridine (1.08 g; 52.3% yield)as an orange crystalline solid. ¹H NMR (CDCl₃) δ 8.68 (d, J=1.6 Hz, 1H,pyridine H6), 7.83 (dd, J=1.6, 8.0 Hz, 1H, pyridine H4), 7.65 (d, J=8.0Hz, 1H, pyridine H3), 3.48 (m, 1H), 3.24 (dd, J=6.8, 10 Hz, 1H),3.09-2.90 (m, 3H), 2.47 (m, 1H), 2.11 (m, 1H). GC-MS (EI): 233 [m]⁺.

(1E)-3-[6-(trifluoromethyl)pyridin-3-yl]tetrahydro-1H-1λ⁴-thien-1-ylidenecyanamide(6) was obtained from5-(tetrahydrothien-3-yl)-2-trifluoro-methylpyridine as an off-whitepowder using the same procedure described in Example III (C) above. The¹H NMR spectrum of this solid exhibited resonances for a 1:1 mixture ofdiastereomers. ¹H NMR (acetone-d₆) δ 8.85 (d, J=2.2 Hz, 1H, pyridineH6), 8.83 (d, J=2.2 Hz, 1H, pyridine H6), 8.26 (dd, J=2.2, 8.3 Hz, 1H,pyridine H4), 8.15 (dd, J=2.2, 8.3 Hz, 1H, pyridine H4), 7.90 (d, J=8.3Hz, 1H, pyridine H3), 7.86 (d, J=8.3 Hz, 1H, pyridine H3), 4.38 (dd,J=8.7, 14 Hz, 1H), 4.23 (tt, J=6, 12 Hz, 1H), 4.16 (ddd, J=2.6, 8.3,11.2 Hz, 1H), 3.83 (td, J=8.7, 18 Hz, 1H), 3.68-3.48 (m, 3H), 3.29-3.17(m, 2H), 2.95 (m, 1H), 2.85-2.79 (m, 3H), 2.33 (m, 1H). LC-MS (ELSD):273 [m]⁺.

Example VII Preparation of[(5-fluoro-6-chloropyridin-3-yl)methyl](methyl)-λ⁴-sulfanylidenecyanamide(7)

A suspension of 2-chloro-3-fluoro-5-methylpyridine (5.1 g, 35 mmol),N-bromosuccinimide (6.1 g, 35 mmol) and benzolyperoxide (0.16 g, 0.66mmol) in carbon tetrachloride (100 mL) was refluxed overnight. Uponcooling down, the solid was filtered off and the filtrate wasconcentrated and loaded onto a silica gel column eluted with 5% EtOAc inhexane to give 3.77 g of the desired2-chloro-3-fluoro-5-bromomethylpyridine as colorless oil in 48% yield.GC-MS calcd. for C₆H₄BrClFN: 224.46. Found: 224.

2-chloro-3-fluoro-5-methylthiomethylpyridine was obtained from2-chloro-3-fluoro-5-bromomethylpyridine using the same proceduredescribed in Example III (B) above. GC-MS calcd. for C₇H₇ClFNS: 191.66.Found: 191.

[(5-fluoro-6-chloropyridin-3-yl)methyl]methyl-λ⁴-sulfanylidenecyanamide(7) was obtained as an off-white solid from2-chloro-3-fluoro-5-methylthio-methylpyridine using the same proceduredescribed in Example III (C). LC-MS calcd. for C₈H₇ClFN₃S [M+1]⁺:232.69. Found: 232.04.

Example VIII Preparation of[(6-(1,1-difluoroethylpyridin-3-yl)methyl](methyl)-λ⁴-sulfanylidenecyanamide(8)

To a solution 5-methyl-2-acetylpyridine (9.9 g, 73.3 mmol) in moleculesieves-dried CH₂Cl₂ (150 mL) was added diethylamino sulfur trifluoride(DAST) (25.8 g, 260 mmol) at room temperature and the mixture wasstirred at room temperature overnight. More DAST (12 g, 74 mmol) wasadded and the reaction continued for two more days after which anadditional DAST (3.8 g, 23 mmol) was added and the reaction continuedfor another 3 days. After the reaction was quenched slowly withsaturated NaHCO₃ at 0° C., the organic phase was separated, dried overNa₂SO₄, filtered, and concentrated. The residue was purified on silicagel eluted with 8% EtOAc in hexane (v/v) to give 3.91 g of2-(1,1-difluoroethyl)-5-methylpyridine (A) as a light brownish oil in34% yield. GC-MS: mass calcd for C₈H₉F₂N [M]⁺ 157. Found 157.

A mixture of 2-(1,1-difluoroethyl)-5-methylpyridine (A) (2.0 g, 12.7mmol), N-bromosuccinimide (2.2 g, 12.7 mmol) and benzoylperoxide (0.15g, 0.63 mmol) in carbon tetrachloride (100 mL) was refluxed overnight.After the solid was removed by filtration, the filtrate wasconcentrated. The residue was re-dissolved in ethanol (40 mL) and sodiumthiomethoxide (1.33 g, 19 mmol) was added at room temperature andstirred for 3 h. The solvent was removed under reduced pressure and theremaining mixture was dissolved in CH₂Cl₂ and water. After separation,the organic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude product 2-(1,1-difluoroethyl)-5-methylthiomethylpyridine (B) was94% pure on GC/MS, which was used directly for the next reaction withoutfurther purification. GC-MS: mass calcd for C₉H₁₁F₂NS [M]⁺ 203. Found203.

[(6-(1,1-difluoroethylpyridin-3-yl)methyl](methyl)-λ⁴-sulfanylidenecyanamide(8) was obtained from 2-(1,1-difluoroethyl)-5-methylthiolmethylpyridine(B) as a brownish solid using the same procedure described in ExampleIII (C). LC-MS: mass calcd for C₁₀H₁₁F₂N₃S [M]⁺ 243.28. Found [M+1]⁺244.11.

Example IX Preparationof_cis-[2-(6-chloropyridin-3-yl)cyclopentyl](methyl)-λ⁴-sulfanylidenecyanamide(9)

5-Bromo-2-chloropyridine (3.0 g, 15.6 mmol) was dissolved in diethylether (100 mL) in an oven-dried, nitrogen-flushed 250 mL round bottomflask and cooled in a dry ice/acetone bath under nitrogen. n-BuLi (1.05g, 16.4 mmol, 6.6 mL of a 2.5 M solution in hexanes) was added viasyringe and the and the orange heterogenous mixture allowed to stir for1 hour. Cyclopentanone (1.3 g, 15.6 mmol) was added via syringe and themixture allowed to warm to −20° C. before being quenched with 1N HCl.The mixture was extracted with EtOAc and the organic extract washed withsat. NaHCO₃. The NaHCO₃ wash was used to neutralize the first aqueouslayer and the combined aqueous layers were extracted with additionalEtOAc and the combined organic layers dried (Na₂SO₄), filtered,concentrated, and purified by flash silica gel chromatography(hexanes:EtOAc; 2:1) to give 1-(6-chloropyridin-3-yl)cyclopentanol (2.33g, 76%) as an off-white solid: mp 92-93° C., LC/MS (ESI) m/z 197, ¹H NMR(300 MHz, CDCl₃) δ 8.50 (d, 1H, J=2.4 Hz), 7.77 (dd, 1H, J=8.4, 2.4 Hz),7.28 (d, 1H, J=8.4 Hz), 2.05-1.80 (m, 8H), 1.60 (s, 1H, OH).

1-(6-Chloropyridin-3-yl)cyclopentanol (2.1 g, 10.5 mmol) was treatedwith acetic acid (12 mL) and sulfuric acid (4 mL) and the mixture heatedto reflux for 30 min. After cooling to room temperature, ice and 2 NNaOH (180 mL) was add and the resulting tan precipitate collected byfiltration, washed with H₂O and dried giving2-chloro-5-(cyclopent-1-enyl)pyridine (1.66 g, 88%) as a tan solid: mp59-60° C., LC/MS (ESI) m/z 179, ¹H NMR (300 MHz, CDCl₃) δ 8.41 (d, 1H,J=2.4 Hz), 7.66 (dd, 1H, J=8.4, 2.4 Hz), 7.25 (d, 1H, J=8.4 Hz), 6.27(t, 1H, J=2.1 Hz), 2.69 (bm, 2H), 2.55 (bm, 2H), 2.05 (m, 2H).

2-Chloro-5-(cyclopent-1-enyl)pyridine (1.5 g, 8.5 mmol) was dissolved inTHF (30 mL) in an oven-dried, nitrogen-flushed 250 mL round bottom flaskand the resulting solution cooled in a dry ice/acetone bath undernitrogen. BH₃.THF complex (2.4 g, 28.0 mmol, 28 mL of a 1 M solution inTHF) was added dropwise with stirring via syringe and the mixture wasallowed to warm slowly to room temperature and stir overnight. 2 N NaOH(15 mL), ethanol (15 mL) and 35% H₂O₂ (10 mL) were added and the mixturestirred for 0.5 h and then diluted with EtOAc and 1 N HCl. The layerswere separated and the organic layer washed with brine and aqueousNaHSO₃, dried over Na₂SO₄, filtered through celite, and concentrated.Purification by flash chromatography (hexanes:EtOAc/10:1→2:1) gave inorder of elution by-products 2-chloro-5-cyclopentylpyridine (0.45 g,29%) and 1-(6-chloropyridin-3-yl)cyclopentanol (0.44 g, 26%) followed bythe desired product trans-2-(6-chloropyridin-3-yl)cyclopentanol (0.25 g,15%) as a clear oil: LC/MS (ESI) m/z 197, ¹H NMR (300 MHz, CDCl₃) δ 8.26(d, 1H, J=2.4 Hz), 7.55 (dd, 1H, J=8.4, 2.4 Hz), 7.25 (d, 1H, J=8.4 Hz),4.12 (m, 1H), 2.88 (m, 1H), 2.24-1.62 (m, 6H).

trans-2-(6-Chloropyridin-3-yl)cyclopentanol (0.225 g, 1.14 mmol) wasdissolved in CH₂Cl₂ (10 mL) in a 50 mL round bottomed flask, thesolution cooled in an ice bath under nitrogen and treated with Et₃N(0.172 g, 1.71 mmol, 0.24 mL) and methanesulfonyl chloride (0.163 g,1.42 mmol, 0.11 ml) via syringe with stirring. After 1 h, TLC(hexanes:EtOAc/2:1) indicated complete conversion. The reaction mixturewas concentrated in vacuo and then partitioned between EtOAc and 1 NHCl. The layers were separated and the organics was dried (Na₂SO₄),filtered and concentrated to give trans-methanesulfonic acid2-(6-chloropyridin-3-yl)cyclopentyl ester (0.303 g, 97%) as an oil:LC/MS (ESI) m/z 275, ¹H NMR (300 MHz, CDCl₃) δ 8.28 (d, 1H, J=2.7 Hz),7.56 (dd, 1H, J=8.1, 2.7 Hz), 7.3 (d, 1H, J=8.1 Hz), 4.93 (apparent q,1H, J=5.7 Hz), 3.28 (apparent q, 1H, J=8.7 Hz), 2.86 (s, 3H), 2.26 (m,2H), 2.10-1.80 (m, 3H), 1.73 (m, 1H).

trans-Methanesulfonic acid 2-(6-chloropyridin-3-yl)cyclopentyl ester(0.295 g, 1.07 mmol) was dissolved in EtOH (5 mL) in a 25 mL roundbottom flask and cooled in an ice bath under nitrogen. Sodium methanethiolate (0.224 g, 3.20 mmol) was added all at once at the cloudy whitemixture was allowed to warm to room temperature and stir overnight. Themixture was diluted with EtOAc and brine and the layers were separated.The organic layer was washed with brine, dried (Na₂SO₄), filtered, andconcentrated. Purification by flash silica gel chromatography(hexanes:EtOAc/10:1) gavecis-2-chloro-5-(2-methylthio-cyclopentyl)pyridine (0.148 g, 61%) as anoil: LC/MS (ESI) m/z 227, ¹H NMR (300 MHz, CDCl₃) δ 8.27 (d, 1H, J=2.7Hz), 7.60 (dd, 1H, J=8.1, 2.7 Hz), 7.26 (d, 1H, J=8.1 Hz), 3.30 (m, 2H),2.24 (m, 1H), 2.15-1.65 (m, 5H), 1.74 (s, 3H).

cis-[2-(6-Chloropyridin-3-yl)cyclopentyl](methyl)-λ⁴-sulfanylidene-cyanamide(9) was obtained as an oily 1:1 mixture of diastereomers fromcis-2-chloro-5-(2-methylthiocyclopentyl)pyridine using the sameprocedure described in Example III (C). LC/MS (ESI) m/z 267, ¹H NMR (300MHz, CDCl₃) δ 8.31 (d, 2H, J=2.7 Hz), 7.70 (dd, 1H, J=8.4, 2.7 Hz), 7.63(dd, 1H, J=8.4, 2.7 Hz), 7.40 (d, 1H, J=8.4 Hz), 7.32 (d, 1H, J=8.4 Hz),3.96 (m, 1H), 3.81 (m, 1H), 3.67-3.51 (m, 2H), 2.73 (s, 3H), 2.59 (m,1H), 2.45 (s, 3H), 2.40-1.95 (m, 9H), 1.85 (m, 2H).

Example X Preparation of[(4,6-dichloropyridin-3-yl)methyl](methyl)-λ⁴-sulfanylidenecyanamide(10)

To a stirred solution of ethyl 4,6-dichloronicotinate (8.8 g, 40 mmol)in anhydrous THF (75 mL) cooled in an ice-water bath was added in adropwise fashion 1 M LiAlH₄ solution in THF (25 mL, 25 mmol). During theaddition, the temperature was not allowed to rise above 25° C. After theaddition was over, the reaction was warmed to 40° C. for 15 min, cooled,then quenched by the successive dropwise addition of water (0.95 mL),15% aqueous NaOH (0.95 mL) and water (1.85 mL). The mixture was filteredthrough celite and the filtrated was dried (MgSO₄), passed through ashort pad of silica gel and concentrated to give a red oil. Ether (100mL) was added whereupon a gummy precipitate immediately appeared whichwas removed by filtration. The ether solution was allowed to stand atroom temperature overnight, during which time more precipitate wasformed which was removed again by filtration. The ether solution wasconcentrated and dried to give 3.25 g of the product2,4-dichloro-5-hydroxy-methylpyridine in 46% yield as a nearly colorlessoily solid. ¹H NMR (300 MHz, CDCl₃) δ 8.5 (s, 1H), 7.4 (s, 1H), 4.8 (s,2H), 2.7 (bs, 1H); GC-MS: mass calcd for C₆H₅Cl₂NO [M]⁺, 177. Found 177.

The starting material 2,4-dichloro-5-hydroxymethylpyridine (3.2 g, 18mmol) was converted into 2.0 g of 2,4-dichloro-5-chloromethylpyridine(57% yield) as a yellow oil using the same procedure as describe inExample II (D). ¹H NMR (300 MHz, CDCl₃) δ 8.4 (s, 1H), 7.4 (s, 1H), 4.7(s, 2H); GC-MS: mass calcd for C₆H₄Cl₃N [M]⁺, 195. Found 195.

2,4-Dichloro-5-methylthiomethylpyridine (2.0 g, 94% yield) was preparedas a yellow oil from 2,4-dichloro-5-chloromethylpyridine (2.0 g, 1.0mmol) by using the same method as described in Example I, procedure A.¹H NMR (300 MHz, CDCl₃) δ 8.3 (s, 1H), 7.4 (s, 1H), 3.7 (s, 2H), 2.0 (s,3H); GC-MS: mass calcd for C₇H₇Cl₂NS [M]⁺, 207. Found 207.

[(4,6-Dichloropyridin-3-yl)methyl](methyl)-λ⁴-sulfanylidene-cyanamide(10) was prepared as a pale yellow gum from2,4-dichloro-5-methylthiomethylpyridine using the same method asdescribed in Example I (B). ¹H NMR (400 MHz, DMSO) δ 8.48 (s, 1H), 7.93(s, 1H), 4.68 (d, 1H), 4.49 (d, 1H), 2.95 (s, 3H); LC-MS (ELSD): masscalcd for C₈H₇Cl₂N₃S [M]⁺ 248. Found 248.

Example XI Insecticidal Testing

The compounds identified in the foregoing examples were tested againstcotton aphid and green peach aphid using procedures describedhereinafter.

Insecticidal Test for Cotton Aphid (Aphis Gossypii) in Foliar SprayAssay

Squash with fully expanded cotyledon leaves were trimmed to onecotyledon per plant and infested with cotton aphid (wingless adult andnymph) 1 day prior to chemical application. Each plant was examinedbefore chemical application to ensure proper infestation (ca. 30-70aphids per plant). Compounds (2 mg) were dissolved in 2 ml ofacetone:methanol (1:1) solvent, forming stock solutions of 1000 ppm. Thestock solutions were diluted 5× with 0.025% Tween 20 in H₂O to obtain asolution at 200 ppm. Lower concentrations (50, 12.5 and 3.13 ppm) wereprepared by making sequential 4× dilutions from the 200 ppm solutionwith a diluent consisting 80 parts of 0.025% Tween 20 in H₂O and 20parts of acetone:methanol (1:1). A hand-held Devilbiss sprayer was usedto apply the spray solutions until runoff to both sides of the squashcotyledon leaves. Four plants (4 replications) were used for eachconcentration of each compound. Reference plants (solvent check) weresprayed with the diluent only. Treated plants were held in a holdingroom for 3 days at approximately 23° C. and 40% RH before the number oflive aphids on each plant was recorded. Insecticidal activity wasmeasured by Corrected % Control using Abbott's correction formula andpresented in Table 1:Corrected % Control=100*(X−Y)/X

-   -   where X=No. of live aphids on solvent check plants        -   Y=No. of live aphids on treated plants            Insecticidal Test for Green Peach Aphid (Myzus Persicae) in            Foliar Spray Assay

Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-50 green peach aphids (wingless adult and nymph) 2-3 days prior tochemical application. Four seedlings were used for each treatment.Compounds (2 mg) were dissolved in 2 ml of acetone:methanol (1:1)solvent, forming stock solutions of 1000 ppm. The stock solutions werediluted 5× with 0.025% Tween 20 in H₂O to obtain a solution at 200 ppm.Lower concentrations (50, 12.5 and 3.13 ppm) were prepared by makingsequential 4× dilutions from the 200 ppm solution with a diluentconsisting 80 parts of 0.025% Tween 20 in H₂O and 20 parts ofacetone:methanol (1:1). A hand-held Devilbiss sprayer was used forspraying a solution to both sides of cabbage leaves until runoff.Reference plants (solvent check) were sprayed with the diluent only.Treated plants were held in a holding room for three days atapproximately 23° C. and 40% RH prior to grading. Evaluation wasconducted by counting the number of live aphids per plant under amicroscope. Insecticidal activity was measured by using Abbott'scorrection formula:Corrected % Control=100*(X−Y)/X

-   -   where X=No. of live aphids on solvent check plants        -   Y=No. of live aphids on treated plants            The Corrected % Control values from assays are given in            Table 1.

TABLE 1 Comp # CA 200 CA 50 GPA 200 GPA 50 1 A D G G 2 A A A A 3 A A A A4 A C F G 5 A E G G 6 A A C E 7 A A C D 8 A A A D 9 D G D G 10 B G G GCA 200 refers to % control at 200 ppm against cotton aphid in foliarspray tests, CA 50 refers to % control at 50 ppm against cotton aphid infoliar spray tests, GPA 200 refers to % control at 200 ppm against greenpeach aphid in foliar spray tests, GPA 50 refers to % control at 50 ppmagainst green peach aphid in foliar spray tests.

In each case of Table 1 the rating scale is as follows:

% Control (or Mortality) Rating  90-100 A 80-89 B 70-79 C 60-69 D 50-59E Less than 50 F Inactive G Not tested HInsecticide Utility

The compounds of the invention are useful for the control ofinvertebrates including insects. Therefore, the present invention alsois directed to a method for inhibiting an insect which comprisesapplying an insect-inhibiting amount of a compound of formula (I) to alocus of the insect, to the area to be protected, or directly on theinsect to be controlled. The compounds of the invention may also be usedto control other invertebrate pests such as mites and nematodes.

The “locus” of insects or other pests is a term used herein to refer tothe environment in which the insects or other pests live or where theireggs are present, including the air surrounding them, the food they eat,or objects which they contact. For example, insects which eat, damage orcontact edible, commodity, ornamental, turf or pasture plants can becontrolled by applying the active compounds to the seed of the plantbefore planting, to the seedling, or cutting which is planted, theleaves, stems, fruits, grain, and/or roots, or to the soil or othergrowth medium before or after the crop is planted. Protection of theseplants against virus, fungus or bacterium diseases may also be achievedindirectly through controlling sap-feeding pests such as whitefly, planthopper, aphid and spider mite. Such plants include those which are bredthrough conventional approaches and which are genetically modified usingmodern biotechnology to gain insect-resistant, herbicide-resistant,nutrition-enhancement, and/or any other beneficial traits.

It is contemplated that the compounds might also be useful to protecttextiles, paper, stored grain, seeds and other foodstuffs, houses andother buildings which may be occupied by humans and/or companion, farm,ranch, zoo, or other animals, by applying an active compound to or nearsuch objects. Domesticated animals, buildings or human beings might beprotected with the compounds by controlling invertebrate and/or nematodepests that are parasitic or are capable of transmitting infectiousdiseases. Such pests include, for example, chiggers, ticks, lice,mosquitoes, flies, fleas and heartworms. Nonagronomic applications alsoinclude invertebrate pest control in forests, in yards, along road sidesand railroad right of way.

The term “inhibiting an insect” refers to a decrease in the numbers ofliving insects, or a decrease in the number of viable insect eggs. Theextent of reduction accomplished by a compound depends, of course, uponthe application rate of the compound, the particular compound used, andthe target insect species. At least an inactivating amount should beused. The term “insect-inactivating amount” is used to describe theamount, which is sufficient to cause a measurable reduction in thetreated insect population. Generally an amount in the range from about 1to about 1000 ppm by weight active compound is used. For example,insects or other pests which can be inhibited include, but are notlimited to:

-   Lepidoptera—Heliothis spp., Helicoverpa spp., Spodoptera spp.,    Mythimna unipuncta, Agrotis ipsilon, Earias spp., Euxoa auxiliaris,    Trichoplusia ni, Anticarsia gemmatalis, Rachiplusia nu, Plutella    xylostella, Chilo spp., Scirpophaga incertulas, Sesamia inferens,    Cnaphalocrocis medinalis, Ostrinia nubilalis, Cydia pomonella,    Carposina niponensis, Adoxophyes orana, Archips argyrospilus,    Pandemis heparana, Epinotia aporema, Eupoecilia ambiguella, Lobesia    botrana, Polychrosis viteana, Pectinophora gossypiella, Pieris    rapae, Phyllonorycter spp., Leucoptera malifoliella, Phyllocnisitis    citrella-   Coleoptera—Diabrotica spp., Leptinotarsa decemlineata, Oulema    oryzae, Anthonomus grandis, Lissorhoptrus oryzophilus, Agriotes    spp., Melanotus communis, Popillia japonica, Cyclocephala spp.,    Tribolium spp.-   Homoptera—Aphis spp., Myzus persicae, Rhopalosiphum spp., Dysaphis    plantaginea, Toxoptera spp., Macrosiphum euphorbiae, Aulacorthum    solani, Sitobion avenae, Metopolophiuim dirhoduim, Schizaphis    graminum, Brachycolus noxius, Nephotettix spp., Nilaparvata lugens,    Sogatellafurcifera, Laodelphax striatellus, Bemisia tabaci,    Trialeurodes vaporariorum, Aleurodes proletella, Aleurothrixus    floccosus, Quadraspidiotus perniciosus, Unaspis yanonensis,    Ceroplastes rubens, Aonidiella aurantii-   Hemiptera—Lygus spp., Eurygaster maura, Nezara viridula, Piezodorus    guildingi, Leptocorisa varicornis, Cimex lectularius, Cimex    hemipterus-   Thysanoptera—Frankliniella spp., Thrips spp., Scirtothrips dorsalis-   Isoptera—Reticulitermes flavipes, Coptotermes formosanus,    Reticulitermes virginicus, Heterotermes aureus, Reticulitermes    hesperus, Coptotermes frenchii, Shedorhinotermes spp.,    Reticulitermes santonensis, Reticulitermes grassei, Reticulitermes    banyulensis, Reticulitermes speratus, Reticulitermes hageni,    Reticulitermes tibialis, Zootermopsis spp., Incisitermes spp.,    Marginitermes spp., Macrotermes spp., Microcerotermes spp.,    Microtermes spp.-   Diptera—Liriomyza spp., Musca domestica, Aedes spp., Culex spp.,    Anopheles spp., Fannia spp., Stomoxys spp.,-   Hymenoptera—Iridomyrmex humilis, Solenopsis spp., Monomorium    pharaonis, Atta spp., Pogonomyrmex spp., Camponotus spp., Monomorium    spp., Tapinoma sessile, Tetramorium spp., Xylocapa spp., Vespula    spp., Polistes spp.-   Mallophaga (chewing lice)-   Anoplura (sucking lice) —Pthirus pubis, Pediculus spp.-   Orthoptera (grasshoppers, crickets)—Melanoplus spp., Locusta    migratoria, Schistocerca gregaria, Gryllotalpidae (mole crickets).-   Blattoidea (cockroaches)—Blatta orientalis, Blattella germanica,    Periplaneta americana, Sipella longipalpa, Periplaneta australasiae,    Periplaneta brunnea, Parcoblatta pennsylvanica, Periplaneta    fuliginosa, Pycnoscelus surinamensis,-   Siphonaptera—Ctenophalides spp., Pulex irritans-   Acari—Tetranychus spp., Panonychus spp., Eotetranychus carpini,    Phyllocoptruta oleivora, Aculus pelekassi, Brevipalpus phoenicis,    Boophilus spp., Dermacentor variabilis, Rhipicephalus sanguineus,    Amblyomma americanum, Ixodes spp., Notoedres cati, Sarcoptes    scabiei, Dermatophagoides spp.-   Nematoda—Dirofilaria immitis, Meloidogyne spp., Heterodera spp.,    Hoplolaimus columbus, Belonolaimus spp., Pratylenchus spp.,    Rotylenchus reniformis, Criconemella ornata, Ditylenchus spp.,    Aphelenchoides besseyi, Hirschmanniella spp.    Compositions

The compounds of this invention are applied in the form of compositionswhich are important embodiments of the invention, and which comprise acompound of this invention and a phytologically-acceptable inertcarrier. Control of the pests is achieved by applying compounds of theinvention in forms of sprays, topical treatment, gels, seed coatings,microcapsulations, systemic uptake, baits, eartags, boluses, foggers,fumigants aerosols, dusts and many others. The compositions are eitherconcentrated solid or liquid formulations which are dispersed in waterfor application, or are dust or granular formulations which are appliedwithout further treatment. The compositions are prepared according toprocedures and formulae which are conventional in the agriculturalchemical art, but which are novel and important because of the presencetherein of the compounds of this invention. Some description of theformulation of the compositions will be given, however, to assure thatagricultural chemists can readily prepare any desired composition.

The dispersions in which the compounds are applied are most oftenaqueous suspensions or emulsions prepared from concentrated formulationsof the compounds. Such water-soluble, water-suspendable or emulsifiableformulations are either solids, usually known as wettable powders, orliquids usually known as emulsifiable concentrates or aqueoussuspensions. Wettable powders, which may be compacted to form waterdispersible granules, comprise an intimate mixture of the activecompound, an inert carrier, and surfactants. The concentration of theactive compound is usually from about 10% to about 90% by weight. Theinert carrier is usually chosen from among the attapulgite clays, themontmorillonite clays, the diatomaceous earths, or the purifiedsilicates. Effective surfactants, comprising from about 0.5% to about10% of the wettable powder, are found among the sulfonated lignins, thecondensed naphthalenesulfonates, the naphthalenesulfonates, thealkylbenzenesulfonates, the alkyl sulfates, and nonionic surfactantssuch as ethylene oxide adducts of alkyl phenols.

Emulsifiable concentrates of the compounds comprise a convenientconcentration of a compound, such as from about 50 to about 500 gramsper liter of liquid, equivalent to about 10% to about 50%, dissolved inan inert carrier which is either a water miscible solvent or a mixtureof water-immiscible organic solvent and emulsifiers. Useful organicsolvents include aromatics, especially the xylenes, and the petroleumfractions, especially the high-boiling naphthalenic and olefinicportions of petroleum such as heavy aromatic naphtha. Other organicsolvents may also be used, such as the terpenic solvents including rosinderivatives, aliphatic ketones such as cyclohexanone, and complexalcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiableconcentrates are chosen from conventional anionic and/or nonionicsurfactants, such as those discussed above.

Aqueous suspensions comprise suspensions of water-insoluble compounds ofthis invention, dispersed in an aqueous vehicle at a concentration inthe range from about 5% to about 50% by weight. Suspensions are preparedby finely grinding the compound, and vigorously mixing it into a vehiclecomprised of water and surfactants chosen from the same types discussedabove. Inert ingredients, such as inorganic salts and synthetic ornatural gums, may also be added, to increase the density and viscosityof the aqueous vehicle. It is often most effective to grind and mix thecompound at the same time by preparing the aqueous mixture, andhomogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer.

The compounds may also be applied as granular compositions, which areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% by weight of the compound,dispersed in an inert carrier which consists entirely or in large partof clay or a similar inexpensive substance. Such compositions areusually prepared by dissolving the compound in a suitable solvent andapplying it to a granular carrier which has been pre-formed to theappropriate particle size, in the range of from about 0.5 to 3 mm. Suchcompositions may also be formulated by making a dough or paste of thecarrier and compound and crushing and drying to obtain the desiredgranular particle size.

Dusts containing the compounds are prepared simply by intimately mixingthe compound in powdered form with a suitable dusty agriculturalcarrier, such as kaolin clay, ground volcanic rock, and the like. Dustscan suitably contain from about 1% to about 10% of the compound.

It is equally practical, when desirable for any reason, to apply thecompound in the form of a solution in an appropriate organic solvent,usually a bland petroleum oil, such as the spray oils, which are widelyused in agricultural chemistry.

Insecticides and acaricides are generally applied in the form of adispersion of the active ingredient in a liquid carrier. It isconventional to refer to application rates in terms of the concentrationof active ingredient in the carrier. The most widely used carrier iswater.

The compounds of the invention can also be applied in the form of anaerosol composition. In such compositions the active compound isdissolved or dispersed in an inert carrier, which is apressure-generating propellant mixture. The aerosol composition ispackaged in a container from which the mixture is dispensed through anatomizing valve. Propellant mixtures comprise either low-boilinghalocarbons, which may be mixed with organic solvents, or aqueoussuspensions pressurized with inert gases or gaseous hydrocarbons.

The actual amount of compound to be applied to loci of insects and mitesis not critical and can readily be determined by those skilled in theart in view of the examples above. In general, concentrations from 10ppm to 5000 ppm by weight of compound are expected to provide goodcontrol. With many of the compounds, concentrations from 100 to 1500 ppmwill suffice.

The locus to which a compound is applied can be any locus inhabited byan insect or mite, for example, vegetable crops, fruit and nut trees,grape vines, ornamental plants, domesticated animals, the interior orexterior surfaces of buildings, and the soil around buildings.

Because of the unique ability of insect eggs to resist toxicant action,repeated applications may be desirable to control newly emerged larvae,as is true of other known insecticides and acaricides.

Systemic movement of compounds of the invention in plants may beutilized to control pests on one portion of the plant by applying thecompounds to a different portion of it. For example, control offoliar-feeding insects can be controlled by drip irrigation or furrowapplication, or by treating the seed before planting. Seed treatment canbe applied to all types of seeds, including those from which plantsgenetically transformed to express specialized traits will germinate.Representative examples include those expressing proteins toxic toinvertebrate pests, such as Bacillus thuringiensis or other insecticidalproteins, those expressing herbicide resistance, such as “RoundupReady®” seed, or those with “stacked” foreign genes expressinginsecticidal proteins, herbicide resistance, nutrition-enhancementand/or any other beneficial traits.

An insecticidal bait composition consisting of compounds of the presentinvention and attractants and/or feeding stimulants may be used toincrease efficacy of the insecticides against insect pest in a devicesuch as trap, bait station, and the like. The bait composition isusually a solid, semi-solid (including gel) or liquid bait matrixincluding the stimulants and one or more non-microencapsulated ormicroencapsulated insecticides in an amount effective to act as killagents.

The compounds of the present invention (Formula I) are often applied inconjunction with one or more other insecticides or fungicides orherbicides to obtain control of a wider variety of pests diseases andweeds. When used in conjunction with other insecticides or fungicides orherbicides, the presently claimed compounds can be formulated with theother insecticides or fungicides or herbicide, tank mixed with the otherinsecticides or fungicides or herbicides, or applied sequentially withthe other insecticides or fungicides or herbicides.

Some of the insecticides that can be employed beneficially incombination with the compounds of the present invention include:antibiotic insecticides such as allosamidin and thuringiensin;macrocyclic lactone insecticides such as spinosad, spinetoram, and otherspinosyns including the 21-butenyl spinosyns and their derivatives;avermectin insecticides such as abamectin, doramectin, emamectin,eprinomectin, ivermectin and selamectin; milbemycin insecticides such aslepimectin, milbemectin, milbemycin oxime and moxidectin; arsenicalinsecticides such as calcium arsenate, copper acetoarsenite, copperarsenate, lead arsenate, potassium arsenite and sodium arsenite;biological insecticides such as Bacillus popilliae, B. sphaericus, B.thuringiensis subsp. aizawai, B. thuringiensis subsp. kurstaki, B.thuringiensis subsp. tenebrionis, Beauveria bassiana, Cydia pomonellagranulosis virus, Douglas fir tussock moth NPV, gypsy moth NPV,Helicoverpa zea NPV, Indian meal moth granulosis virus, Metarhiziumanisopliae, Nosema locustae, Paecilomyces fumosoroseus, P. lilacinus,Photorhabdus luminescens, Spodoptera exigua NPV, trypsin modulatingoostatic factor, Xenorhabdus nematophilus, and X. bovienii, plantincorporated protectant insecticides such as Cry1Ab, Cry1Ac, Cry1F,Cry1A.105, Cry2Ab2, Cry3A, mir Cry3A, Cry3B1, Cry34, Cry35, and VIP3A;botanical insecticides such as anabasine, azadirachtin, d-limonene,nicotine, pyrethrins, cinerins, cinerin I, cinerin II, jasmolin I,jasmolin II, pyrethrin I, pyrethrin II, quassia, rotenone, ryania andsabadilla; carbamate insecticides such as bendiocarb and carbaryl;benzofuranyl methylcarbamate insecticides such as benfuracarb,carbofuran, carbosulfan, decarbofuran and furathiocarb;dimethylcarbamate insecticides dimitan, dimetilan, hyquincarb andpirimicarb; oxime carbamate insecticides such as alanycarb, aldicarb,aldoxycarb, butocarboxim, butoxycarboxim, methomyl, nitrilacarb, oxamyl,tazimcarb, thiocarboxime, thiodicarb and thiofanox; phenylmethylcarbamate insecticides such as allyxycarb, aminocarb, bufencarb,butacarb, carbanolate, cloethocarb, dicresyl, dioxacarb, EMPC,ethiofencarb, fenethacarb, fenobucarb, isoprocarb, methiocarb,metolcarb, mexacarbate, promacyl, promecarb, propoxur, trimethacarb, XMCand xylylcarb; dinitrophenol insecticides such as dinex, dinoprop,dinosam and DNOC; fluorine insecticides such as bariumhexafluorosilicate, cryolite, sodium fluoride, sodium hexafluorosilicateand sulfluramid; formamidine insecticides such as amitraz,chlordimeform, formetanate and formparanate; fumigant insecticides suchas acrylonitrile, carbon disulfide, carbon tetrachloride, chloroform,chloropicrin, para-dichlorobenzene, 1,2-dichloropropane, ethyl formate,ethylene dibromide, ethylene dichloride, ethylene oxide, hydrogencyanide, iodomethane, methyl bromide, methylchloroform, methylenechloride, naphthalene, phosphine, sulfuryl fluoride andtetrachloroethane; inorganic insecticides such as borax, calciumpolysulfide, copper oleate, mercurous chloride, potassium thiocyanateand sodium thiocyanate; chitin synthesis inhibitors such asbistrifluoron, buprofezin, chlorfluazuron, cyromazine, diflubenzuron,flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron,noviflumuron, penfluoron, teflubenzuron and triflumuron; juvenilehormone mimics such as epofenonane, fenoxycarb, hydroprene, kinoprene,methoprene, pyriproxyfen and triprene; juvenile hormones such asjuvenile hormone I, juvenile hormone II and juvenile hormone III;moulting hormone agonists such as chromafenozide, halofenozide,methoxyfenozide and tebufenozide; moulting hormones such as α-ecdysoneand ecdysterone; moulting inhibitors such as diofenolan; precocenes suchas precocene I, precocene II and precocene III; unclassified insectgrowth regulators such as dicyclanil; nereistoxin analogue insecticidessuch as bensultap, cartap, thiocyclam and thiosultap; nicotinoidinsecticides such as flonicamid; nitroguanidine insecticides such asclothianidin, dinotefuran, imidacloprid and thiamethoxam; nitromethyleneinsecticides such as nitenpyram and nithiazine; pyridylmethylamineinsecticides such as acetamiprid; imidacloprid, nitenpyram andthiacloprid; organochlorine insecticides such as bromo-DDT, camphechlor,DDT, pp′-DDT, ethyl-DDD, HCH, gamma-HCH, lindane, methoxychlor,pentachlorophenol and TDE; cyclodiene insecticides such as aldrin,bromocyclen, chlorbicyclen, chlordane, chlordecone, dieldrin, dilor,endosulfan, endrin, HEOD, heptachlor, HHDN, isobenzan, isodrin, kelevanand mirex; organophosphate insecticides such as bromfenvinfos,chlorfenvinphos, crotoxyphos, dichlorvos, dicrotophos, dimethylvinphos,fospirate, heptenophos, methocrotophos, mevinphos, monocrotophos, naled,naftalofos, phosphamidon, propaphos, TEPP and tetrachlorvinphos;organothiophosphate insecticides such as dioxabenzofos, fosmethilan andphenthoate; aliphatic organothiophosphate insecticides such as acethion,amiton, cadusafos, chlorethoxyfos, chlormephos, demephion, demephion-O,demephion-S, demeton, demeton-O, demeton-S, demeton-methyl,demeton-O-methyl, demeton-S-methyl, demeton-S-methylsulphon, disulfoton,ethion, ethoprophos, IPSP, isothioate, malathion, methacrifos,oxydemeton-methyl, oxydeprofos, oxydisulfoton, phorate, sulfotep,terbufos and thiometon; aliphatic amide organothiophosphate insecticidessuch as amidithion, cyanthoate, dimethoate, ethoate-methyl, formothion,mecarbam, omethoate, prothoate, sophamide and vamidothion; oximeorganothiophosphate insecticides such as chlorphoxim, phoxim andphoxim-methyl; heterocyclic organothiophosphate insecticides such asazamethiphos, coumaphos, coumithoate, dioxathion, endothion, menazon,morphothion, phosalone, pyraclofos, pyridaphenthion and quinothion;benzothiopyran organothiophosphate insecticides such as dithicrofos andthicrofos; benzotriazine organothiophosphate insecticides such asazinphos-ethyl and azinphos-methyl; isoindole organothiophosphateinsecticides such as dialifos and phosmet; isoxazole organothiophosphateinsecticides such as isoxathion and zolaprofos; pyrazolopyrimidineorganothiophosphate insecticides such as chlorprazophos and pyrazophos;pyridine organothiophosphate insecticides such as chlorpyrifos andchlorpyrifos-methyl; pyrimidine organothiophosphate insecticides such asbutathiofos, diazinon, etrimfos, lirimfos, pirimiphos-ethyl,pirimiphos-methyl, primidophos, pyrimitate and tebupirimfos; quinoxalineorganothiophosphate insecticides such as quinalphos andquinalphos-methyl; thiadiazole organothiophosphate insecticides such asathidathion, lythidathion, methidathion and prothidathion; triazoleorganothiophosphate insecticides such as isazofos and triazophos; phenylorganothiophosphate insecticides such as azothoate, bromophos,bromophos-ethyl, carbophenothion, chlorthiophos, cyanophos, cythioate,dicapthon, dichlofenthion, etaphos, famphur, fenchlorphos, fenitrothionfensulfothion, fenthion, fenthion-ethyl, heterophos, jodfenphos,mesulfenfos, parathion, parathion-methyl, phenkapton, phosnichlor,profenofos, prothiofos, suiprofos, temephos, trichlormetaphos-3 andtrifenofos; phosphonate insecticides such as butonate and trichlorfon;phosphonothioate insecticides such as mecarphon; phenylethylphosphonothioate insecticides such as fonofos and trichloronat;phenyl phenylphosphonothioate insecticides such as cyanofenphos, EPN andleptophos; phosphoramidate insecticides such as crufomate, fenamiphos,fosthietan, mephosfolan, phosfolan and pirimetaphos;phosphoramidothioate insecticides such as acephate, isocarbophos,isofenphos, methamidophos and propetamphos; phosphorodiamideinsecticides such as dimefox, mazidox, mipafox and schradan; oxadiazineinsecticides such as indoxacarb; phthalimide insecticides such asdialifos, phosmet and tetramethrin; pyrazole insecticides such asacetoprole, ethiprole, fipronil, pyrafluprole, pyriprole, tebufenpyrad,tolfenpyrad and vaniliprole; pyrethroid ester insecticides such asacrinathrin, allethrin, bioallethrin, barthrin, bifenthrin,bioethanomethrin, cyclethrin, cycloprothrin, cyfluthrin,beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin,cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin,zeta-cypermethrin, cyphenothrin, deltamethrin, dimefluthrin, dimethrin,empenthrin, fenfluthrin, fenpirithrin, fenpropathrin, fenvalerate,esfenvalerate, flucythrinate, fluvalinate, tau-fluvalinate, furethrin,imiprothrin, metofluthrin, permethrin, biopermethrin, transpermethrin,phenothrin, prallethrin, profluthrin, pyresmethrin, resmethrin,bioresmethrin, cismethrin, tefluthrin, terallethrin, tetramethrin,tralomethrin and transfluthrin; pyrethroid ether insecticides such asetofenprox, flufenprox, halfenprox, protrifenbute and silafluofen;pyrimidinamine insecticides such as flufenerim and pyrimidifen; pyrroleinsecticides such as chlorfenapyr; tetronic acid insecticides such asspirodiclofen, spiromesifen and spirotetramat; thiourea insecticidessuch as diafenthiuron; urea insecticides such as flucofuron andsulcofuron; and unclassified insecticides such as AKD-3088, closantel,crotamiton, cyflumetofen, E2Y45, EXD, fenazaflor, fenazaquin,fenoxacrim, fenpyroximate, FKI-1033, flubendiamide, HGW86,hydramethylnon, IKI-2002, isoprothiolane, malonoben, metaflumizone,metoxadiazone, nifluridide, NNI-9850, NNI-0101, pymetrozine, pyridaben,pyridalyl, Qcide, rafoxanide, rynaxypyr, SYJ-159, triarathene andtriazamate and any combinations thereof.

Some of the fungicides that can be employed beneficially in combinationwith the compounds of the present invention include:2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol,8-hydroxyquinoline sulfate, Ampelomyces, quisqualis, azaconazole,azoxystrobin, Bacillus subtilis, benalaxyl, benomyl,benthiavalicarb-isopropyl, benzylaminobenzene-sulfonate (BABS) salt,bicarbonates, biphenyl, bismerthiazol, bitertanol, blasticidin-S, borax,Bordeaux mixture, boscalid, bromuconazole, bupirimate, calciumpolysulfide, captafol, captan, carbendazim, carboxin, carpropamid,carvone, chloroneb, chlorothalonil, chlozolinate, Coniothyrium minitans,copper hydroxide, copper octanoate, copper oxychloride, copper sulfate,copper sulfate (tribasic), cuprous oxide, cyazofamid, cyflufenamid,cymoxanil, cyproconazole, cyprodinil, dazomet, debacarb, diammoniumethylenebis-(dithiocarbamate), dichlofluanid, dichlorophen, diclocymet,diclomezine, dichloran, diethofencarb, difenoconazole, difenzoquat ion,diflumetorim, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M,dinobuton, dinocap, diphenylamine, dithianon, dodemorph, dodemorphacetate, dodine, dodine free base, edifenphos, epoxiconazole, ethaboxam,ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil,fenpropidin, fenpropimorph, fentin, fentin acetate, fentin hydroxide,ferbam, ferimzone, fluazinam, fludioxonil, flumorph, fluopicolide,fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide,flutolanil, flutriafol, folpet, formaldehyde, fosetyl,fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine,guazatine acetates, GY-81, hexachlorobenzene, hexaconazole, hymexazol,imazalil, imazalil sulfate, imibenconazole, iminoctadine, iminoctadinetriacetate, iminoctadine tris(albesilate), ipconazole, iprobenfos,iprodione, iprovalicarb, isoprothiolane, kasugamycin, kasugamycinhydrochloride hydrate, kresoxim-methyl, mancopper, mancozeb, maneb,mepanipyrim, mepronil, mercuric chloride, mercuric oxide, mercurouschloride, metalaxyl, mefenoxam, metalaxyl-M, metam, metam-ammonium,metam-potassium, metam-sodium, metconazole, methasulfocarb, methyliodide, methyl isothiocyanate, metiram, metominostrobin, metrafenone,mildiomycin, myclobutanil, nabam, nitrothal-isopropyl, nuarimol,octhilinone, ofurace, oleic acid (fatty acids), orysastrobin, oxadixyl,oxine-copper, oxpoconazole fumarate, oxycarboxin, pefurazoate,penconazole, pencycuron, pentachlorophenol, pentachlorophenyl laurate,penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide,picoxystrobin, polyoxin B, polyoxins, polyoxorim, potassium bicarbonate,potassium hydroxyquinoline sulfate, probenazole, prochloraz,procymidone, propamocarb, propamocarb hydrochloride, propiconazole,propineb, proquinazid, prothioconazole, pyraclostrobin, pyrazophos,pyributicarb, pyrifenox, pyrimethanil, pyroquilon, quinoclamine,quinoxyfen, quintozene, Reynoutria sachalinensis extract, silthiofam,simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodiumpentachlorophenoxide, spiroxamine, sulfur, SYP-Z071, tar oils,tebuconazole, tecnazene, tetraconazole, thiabendazole, thifluzamide,thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolylfluanid,triadimefon, triadimenol, triazoxide, tricyclazole, tridemorph,trifloxystrobin, triflumizole, triforine, triticonazole, validamycin,vinclozolin, zineb, ziram, zoxamide, Candida oleophila, Fusariumoxysporum, Gliocladium spp., Phlebiopsis gigantean, Streptomycesgriseoviridis, Trichoderma spp.,(RS)—N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide,1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate,1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane,2-(2-heptadecyl-2-imidazolin-1-yl)ethanol,2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide,2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5-methylrhodanine,4-(2-nitroprop-1-enyl)phenyl thiocyanateme: ampropylfos, anilazine,azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox,bentaluron, benzamacril; benzamacril-isobutyl, benzamorf, binapacryl,bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmiumcalcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone,chloraniformethan, chlorfenazole, chlorquinox, climbazole, copperbis(3-phenylsalicylate), copper zinc chromate, cufraneb, cuprichydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, cyprofuram,decafentin, dichlone, dichlozoline, diclobutrazol, dimethirimol,dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin,drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf,fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole,furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin,halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos,isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam,methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride,myclozolin, N-3,5-dichlorophenyl-succinimide,N-3-nitrophenylitaconimide, natamycin,N-ethylmercurio-4-toluenesulfonanilide, nickelbis(dimethyldithiocarbamate), OCH, phenylmercurydimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb;prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor,pyroxyfur, quinacetol; quinacetol sulfate, quinazamid, quinconazole,rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor,thicyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid,triamiphos, triarimol, triazbutil, trichlamide, urbacid, XRD-563, andzarilamid, and any combinations thereof.

Some of the herbicides that can be employed in conjunction with thecompounds of the present invention include: amide herbicides such asallidochlor, beflubutamid, benzadox, benzipram, bromobutide,cafenstrole, CDEA, chlorthiamid, cyprazole, dimethenamid,dimethenamid-P, diphenamid, epronaz, etnipromid, fentrazamide, flupoxam,fomesafen, halosafen, isocarbamid, isoxaben, napropamide, naptalam,pethoxamid, propyzamide, quinonamid and tebutam; anilide herbicides suchas chloranocryl, cisanilide, clomeprop, cypromid, diflufenican,etobenzanid, fenasulam, flufenacet, flufenican, mefenacet, mefluidide,metamifop, monalide, naproanilide, pentanochlor, picolinafen andpropanil; arylalanine herbicides such as benzoylprop, flampropandflamprop-M; chloroacetanilide herbicides such as acetochlor, alachlor,butachlor, butenachlor, delachlor, diethatyl, dimethachlor, metazachlor,metolachlor, S-metolachlor, pretilachlor, propachlor, propisochlor,prynachlor, terbuchlor, thenylchlor and xylachlor; sulfonanilideherbicides such as benzofluor, perfluidone, pyrimisulfan and profluazol;sulfonamide herbicides such as asulam, carbasulam, fenasulam andoryzalin; antibiotic herbicides such as bilanafos; benzoic acidherbicides such as chloramben, dicamba, 2,3,6-TBA and tricamba;pyrimidinyloxybenzoic acid herbicides such as bispyribac andpyriminobac; pyrimidinylthiobenzoic acid herbicides such as pyrithiobac;phthalic acid herbicides such as chlorthal; picolinic acid herbicidessuch as aminopyralid, clopyralid and picloram; quinolinecarboxylic acidherbicides such as quinclorac and quinmerac; arsenical herbicides suchas cacodylic acid, CMA, DSMA, hexaflurate, MAA, MAMA, MSMA, potassiumarsenite and sodium arsenite; benzoylcyclohexanedione herbicides such asmesotrione, sulcotrione, tefuryltrione and tembotrione; benzofuranylalkylsulfonate herbicides such as benfuresate and ethofumesate;carbamate herbicides such as asulam, carboxazole chlorprocarb,dichlormate, fenasulam, karbutilate and terbucarb; carbanilateherbicides such as barban, BCPC, carbasulam, carbetamide, CEPC,chlorbufam, chlorpropham, CPPC, desmedipham, phenisopham, phenmedipham,phenmedipham-ethyl, propham and swep; cyclohexene oxime herbicides suchas alloxydim, butroxydim, clethodim, cloproxydim, cycloxydim,profoxydim, sethoxydim, tepraloxydim and tralkoxydim;cyclopropylisoxazole herbicides such as isoxachlortole and isoxaflutole;dicarboximide herbicides such as benzfendizone, cinidon-ethyl, flumezin,flumiclorac, flumioxazin and flumipropyn; dinitroaniline herbicides suchas benfluralin, butralin, dinitramine, ethalfluralin, fluchloralin,isopropalin, methalpropalin, nitralin, oryzalin, pendimethalin,prodiamine, profluralin and trifluralin; dinitrophenol herbicides suchas dinofenate, dinoprop, dinosam, dinoseb, dinoterb, DNOC, etinofen andmedinoterb; diphenyl ether herbicides such as ethoxyfen; nitrophenylether herbicides such as acifluorfen, aclonifen, bifenox,chlomethoxyfen, chlornitrofen, etnipromid, fluorodifen, fluoroglycofen,fluoronitrofen, fomesafen, furyloxyfen, halosafen, lactofen, nitrofen,nitrofluorfen and oxyfluorfen; dithiocarbamate herbicides such asdazomet and metam; halogenated aliphatic herbicides such as alorac,chloropon, dalapon, flupropanate, hexachloroacetone, iodomethane, methylbromide, monochloroacetic acid, SMA and TCA; imidazolinone herbicidessuch as imazamethabenz, imazamox, imazapic, imazapyr, imazaquin andimazethapyr; inorganic herbicides such as ammonium sulfamate, borax,calcium chlorate, copper sulfate, ferrous sulfate, potassium azide,potassium cyanate, sodium azide, sodium chlorate and sulfuric acid;nitrile herbicides such as bromobonil, bromoxynil, chloroxynil,dichlobenil, iodobonil, ioxynil and pyraclonil; organophosphorusherbicides such as amiprofos-methyl, anilofos, bensulide, bilanafos,butamifos, 2,4-DEP, DMPA, EBEP, fosamine, glufosinate, glyphosate andpiperophos; phenoxy herbicides such as bromofenoxim, clomeprop, 2,4-DEB,2,4-DEP, difenopenten, disul, erbon, etnipromid, fenteracol andtrifopsime; phenoxyacetic herbicides such as 4-CPA, 2,4-D, 3,4-DA, MCPA,MCPA-thioethyl and 2,4,5-T; phenoxybutyric herbicides such as 4-CPB,2,4-DB, 3,4-DB, MCPB and 2,4,5-TB; phenoxypropionic herbicides such ascloprop, 4-CPP, dichlorprop, dichlorprop-P, 3,4-DP, fenoprop, mecopropand mecoprop-P; aryloxyphenoxypropionic herbicides such as chlorazifop,clodinafop, clofop, cyhalofop, diclofop, fenoxaprop, fenoxaprop-P,fenthiaprop, fluazifop, fluazifop-P, haloxyfop, haloxyfop-P,isoxapyrifop, metamifop, propaquizafop, quizalofop, quizalofop-P andtrifop; phenylenediamine herbicides such as dinitramine and prodiamine;pyrazolyl herbicides such as benzofenap, pyrazolynate, pyrasulfotole,pyrazoxyfen, pyroxasulfone and topramezone; pyrazolylphenyl herbicidessuch as fluazolate and pyraflufen; pyridazine herbicides such ascredazine, pyridafol and pyridate; pyridazinone herbicides such asbrompyrazon, chloridazon, dimidazon, flufenpyr, metflurazon,norflurazon, oxapyrazon and pydanon; pyridine herbicides such asaminopyralid, cliodinate, clopyralid, dithiopyr, fluoroxypyr,haloxydine, picloram, picolinafen, pyriclor, thiazopyr and triclopyr;pyrimidinediamine herbicides such as iprymidam and tioclorim; quaternaryammonium herbicides such as cyperquat, diethamquat, difenzoquat, diquat,morfamquat and paraquat; thiocarbamate herbicides such as butylate,cycloate, di-allate, EPTC, esprocarb, ethiolate, isopolinate,methiobencarb, molinate, orbencarb, pebulate, prosulfocarb,pyributicarb, sulfallate, thiobencarb, tiocarbazil, tri-allate andvernolate; thiocarbonate herbicides such as dimexano, EXD and proxan;thiourea herbicides such as methiuron; triazine herbicides such asdipropetryn, triaziflam and trihydroxytriazine; chlorotriazineherbicides such as atrazine, chlorazine, cyanazine, cyprazine,eglinazine, ipazine, mesoprazine, procyazine, proglinazine, propazine,sebuthylazine, simazine, terbuthylazine and trietazine; methoxytriazineherbicides such as atraton, methometon, prometon, secbumeton, simetonand terbumeton; methylthiotriazine herbicides such as ametryn,aziprotryne, cyanatryn, desmetryn, dimethametryn, methoprotryne,prometryn, simetryn and terbutryn; triazinone herbicides such asametridione, amibuzin, hexazinone, isomethiozin, metamitron andmetribuzin; triazole herbicides such as amitrole, cafenstrole, epronazand flupoxam; triazolone herbicides such as amicarbazone, bencarbazone,carfentrazone, flucarbazone, propoxycarbazone, sulfentrazone andthiencarbazone-methyl; triazolopyrimidine herbicides such ascloransulam, diclosulam, florasulam, flumetsulam, metosulam, penoxsulamand pyroxsulam; uracil herbicides such as butafenacil, bromacil,flupropacil, isocil, lenacil and terbacil; 3-phenyluracils; ureaherbicides such as benzthiazuron, cumyluron, cycluron, dichloralurea,diflufenzopyr, isonoruron, isouron, methabenzthiazuron, monisouron andnoruron; phenylurea herbicides such as anisuron, buturon, chlorbromuron,chloreturon, chlorotoluron, chloroxuron, daimuron, difenoxuron,dimefuron, diuron, fenuron, fluometuron, fluothiuron, isoproturon,linuron, methiuron, methyldymron, metobenzuron, metobromuron, metoxuron,monolinuron, monuron, neburon, parafluoron, phenobenzuron, siduron,tetrafluoron and thidiazuron; pyrimidinylsulfonylurea herbicides such asamidosulfuron, azimsulfuron, bensulfuron, chlorimuron, cyclosulfamuron,ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron,foramsulfuron, halosulfuron, imazosulfuron, mesosulfuron, nicosulfuron,orthosulfamuron, oxasulfuron, primisulfuron, pyrazosulfuron,rimsulfuron, sulfometuron, sulfosulfuron and trifloxysulfuron;triazinylsulfonylurea herbicides such as chlorsulfuron, cinosulfuron,ethametsulfuron, iodosulfuron, metsulfuron, prosulfuron, thifensulfuron,triasulfuron, tribenuron, triflusulfuron and tritosulfuron;thiadiazolylurea herbicides such as buthiuron, ethidimuron, tebuthiuron,thiazafluoron and thidiazuron; and unclassified herbicides such asacrolein, allyl alcohol, azafenidin, benazolin, bentazone,benzobicyclon, buthidazole, calcium cyanamide, cambendichlor,chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol, cinmethylin,clomazone, CPMF, cresol, ortho-dichlorobenzene, dimepiperate, endothal,fluorornidine, fluridone, fluorochloridone, flurtamone, fluthiacet,indanofan, methazole, methyl isothiocyanate, nipyraclofen, OCH,oxadiargyl, oxadiazon, oxaziclomefone, pentachlorophenol, pentoxazone,phenylmercury acetate, pinoxaden, prosulfalin, pyribenzoxim, pyriftalid,quinoclamine, rhodethanil, sulglycapin, thidiazimin, tridiphane,trimeturon, tripropindan and tritac.

1. Compounds of the formula (I)

wherein Het represents:

X represents halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₂-C₄ haloalkenyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, CN, NO₂,COOR⁴ or CONR⁴R⁵; Y represents hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkenyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, CN, NO₂, COOR⁴, CONR⁴R⁵, or aryl; Z representsC₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkenyl, C₁-C₄haloalkoxy, CN, NO₂, COOR⁴ or CONR⁴R⁵; n is an integer from 0-3; Lrepresents either a single bond or —CH₂—; R¹ represents C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ haloalkenyl,arylalkyl; R² and R³ independently represent hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkenyl,C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, CN, SO_(m)R⁶ where m is an integer from0-2, arylalkyl, or, alternatively, R² and R³ and the common carbon towhich they attach form a 3-6 membered ring; R⁴ and R⁵ independentlyrepresent hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl; C₃-C₆ alkenyl, C₃-C₆alkynyl, C₃-C₆ haloalkenyl, aryl, or arylalkyl; R⁶ represents C₁-C₄alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ haloalkenyl,or arylalkyl; and Q represents NO₂ or CN.
 2. A compound of claim 1 inwhich Q represents CN.
 3. A compound of claim 1 in which R² and R³independently represent hydrogen or C₁-C₄ alkyl or R² and R³ and thecommon carbon to which they attach form a 3-6 membered ring.
 4. Acompound of claim 1 in which Het represents

wherein Y represents hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkenyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, CN, NO₂, COOR⁴, CONR⁴R⁵, or aryl; and Z represents C₁-C₄haloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkenyl, C₁-C₄haloalkoxy, CN, NO₂, COOR⁴ or CONR⁴R⁵.
 5. A compound of claim 4 in whichY represents hydrogen and Z represents C₁-C₂ haloalkyl.
 6. A compound ofclaim 1 having the formula

wherein Het, Q, R² and R³ are as previously defined.
 7. A compositionfor controlling insects which comprises a compound of claim 1 incombination with a phytologically-acceptable carrier.
 8. A method ofcontrolling insects which comprises applying to a locus where control isdesired an insect-inactivating amount of a compound of claim 1.